tbuckley/cabot-search huggingface dataset:
Artificial intelligence-powered human epidermal growth factor receptor 2 (HER2) analyzer in breast cancer as an assistance tool for pathologists to reduce interobserver variation.
Authors: Minsun Jung, Seung Geun Song, Soo Ick Cho, Wonkyung Jung, Chiyoon Oum, Heon Song, Minuk Ma, Seonwook Park, Sergio Pereira, Sanghoon Song, Kyunghyun Paeng, Donggeun Yoo, Chan-Young Ock, Ji-Youn Sung, So-Woon Kim
Journal: Journal of Clinical Oncology (2022)

e12543 Background: Human epidermal growth factor receptor 2 (HER2) expression is a predictive marker for HER2-targeted therapy in breast cancer patients. Interobserver variation in the interpretation of HER2 levels exists among pathologists, thus a method to increase the consistency of evaluation is needed. This study aimed to evaluate the performance of the artificial intelligence (AI)-based Lunit SCOPE HER2 in assisting pathologists to evaluate HER2 expression levels in breast cancer. Methods: Lunit SCOPE HER2 was developed with a 1.04 x 10 10 μm 2 area and 7.31 x 10 5 tumor cells from 1,133 HER2 immunohistochemistry stained whole-slide images (WSI) of breast cancer, annotated by 113 board-certified pathologists. The AI model was developed based on a semantic segmentation algorithm, which consists of two atrous spatial pyramid pooling blocks for tissue level classification and for tumor cell level classification. To validate the model, a total of 209 HER2 WSIs diagnosed with breast cancer were obtained from Kyung Hee University Hospital in Korea and were assigned as an external validation set. Three board-certified pathologists evaluated slide level HER2 expression (3+, 2+, 1+, and 0) twice, first without AI assistance and second, with it. The second reading was performed for WSIs where the pathologist's reading showed discrepancy with the AI model. Results: In the external validation set, all pathologists scored the same HER2 grade in 103 WSIs (49.3%), and the Fleiss kappa value was 0.512. The HER2 grade from the AI model and pathologists was the same in 151 WSIs (72.2%), and the weighted kappa value was 0.844. The pathologists re-evaluate 43, 63, and 83 WSIs, respectively. After AI assistance, all pathologists scored the same HER2 grade in 156 WSIs (74.6%), and the Fleiss kappa value increased to 0.762 (Table). Conclusions: This study demonstrates that an AI-powered HER2 analyzer can help achieve consistent HER2 expression level evaluation in breast cancer by reducing interobserver variability. Thus, the AI model can be applied as an assistance tool for pathologists in HER2 grade evaluation.[Table: see text]
The association of germline<i> HSD3B1</i> genotype with outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT) with or without enzalutamide (ENZA) [ARCHES].
Authors: Nima Sharifi, Arun Azad, Mona Patel, Jason W.D. Hearn, Michele Wozniak, Fabian Zohren, Jennifer Sugg, Gabriel P. Haas, Arnulf Stenzl, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2022)

5022 Background: A common missense-encoding germline polymorphism in HSD3B1(1245A→C) stabilizes the 3βHSD1 enzyme and increases the rate-limiting step for metabolic flux from adrenal precursors to potent androgens. This adrenal-permissive HSD3B1(1245C) allele mechanistically drives more rapid progression after ADT in nonmetastatic and low-volume (LV) mHSPC. It is unknown whether upfront treatment with ENZA could improve these poor outcomes. We sought to determine the association between the HSD3B1 genotype and outcomes in ARCHES, a randomized, placebo (PBO)-controlled, phase 3 global study of ADT with ENZA or PBO in mHSPC. Overall, 31.3% of men on placebo crossed over to ENZA prior to progression. Methods: Germline DNA from 660 men (243 LV and 417 high volume [HV]) in ARCHES was genotyped for HSD3B1. Radiographic progression-free survival (rPFS), prostate-specific antigen (PSA) outcomes, and overall survival (OS) were compared between men who inherited 0 (adrenal restrictive) vs. 1–2 copies of the HSD3B1(1245C) allele (adrenal permissive) using log-rank tests, Kaplan-Meier estimates, and Cox proportional hazards models for hazard ratios (HRs). Results: In ARCHES, 340 and 320 men had the adrenal-restrictive and adrenal-permissive HSD3B1 genotype, respectively. The adrenal-permissive genotype was not associated with worse rPFS, time to PSA progression (TTPP), or OS. Cox model HRs for death in the adrenal-permissive compared with adrenal-restrictive men in the ENZA + ADT and PBO + ADT arms were 1.21 (95% confidence interval [CI] 0.84, 1.74) and 1.48 (95% CI 0.98, 2.25), respectively. Three-year OS was 82% and 73% in men treated with ENZA + ADT with restrictive vs. permissive genotypes, respectively, and 68% and 70% in men treated with PBO + ADT. ENZA significantly improved rPFS, TTPP, and OS, irrespective of genotype. HRs for ENZA + ADT vs. PBO + ADT in models adjusted for genotype were: rPFS, 0.64 (p &lt; 0.001); TTPP, 0.27 (p &lt; 0.001), and OS, 0.62 (p &lt; 0.001). Of OS events in the HSD3B1-genotyped men, 48 (23%) and 163 (77%) deaths occurred in the LV and HV groups, respectively. Conclusions: In men with mHSPC, ENZA improved OS, rPFS, and TTPP over PBO + ADT, irrespective of HSD3B1 genotype. Survival analysis of HSD3B1-genotyped men in this study is largely driven by men with HV disease. The analysis of men with LV disease was limited by the small number of events. Clinical trial information: NCT02677896.
Pfizer pledges to provide 23 drugs at not-for-profit prices to lower income countries
Authors: Janice Hopkins Tanne
Journal: BMJ (2022)

<h3>Abstract</h3> Sustained minimal residual disease (MRD) negativity is associated with long-term survival in multiple myeloma (MM). The gut microbiome is affected by diet, and in turn can modulate host immunity, for example through production of short-chain fatty acids including butyrate. We examined the relationship of dietary factors, stool metabolites, and microbial diversity with sustained MRD negativity in patients on lenalidomide maintenance. At 3 months, higher stool butyrate concentration (p=0.037), butyrate producers (p=0.025) and α-diversity (p=0.0035) were associated with sustained MRD-negativity. Healthier dietary proteins, (from seafood and plants), correlated with butyrate at 3 months (p=0.009) and sustained MRD-negativity (p=0.05). Consumption of dietary flavonoids, plant nutrients with antioxidant effects, correlated with stool butyrate concentration (anthocyanidins p=0.01, flavones p=0.01, and flavanols p=0.02). This is the first study to demonstrate an association between a plant-based dietary pattern, stool butyrate production and sustained MRD-negativity in MM; providing rationale to evaluate a prospective dietary intervention. <h3>Statement of Significance</h3> We demonstrate an association between diet, the gut microbiome, and sustained MRD-negativity in MM. A healthy diet, with adequate plant and seafood protein, and containing flavonoids, associates with stool diversity, butyrate production and sustained MRD-negativity. These findings suggest dietary modification should be studied to enhance myeloma control. <h3>Key Points</h3> In MM on lenalidomide maintenance, stool butyrate concentration at 3 months was associated with higher rates of MRD negativity at 12 months. Increased seafood and plant proteins, dietary flavonoids, and diversity of dietary flavonoids correlated with stool butyrate concentrations.
Aneurysmal cyclic circumferential stretch affects the expression of endothelial genes involved in vascular homeostasis
Authors: MR Diagbouga, S Morel, S Lemeille, BR Kwak
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Background Intracranial aneurysm (IA) rupture is a common cause of hemorrhagic stroke. IAs are present in 3 to 5% of the general population and the annual rupture rate of an IA has been estimated to 1%. Once formed, an IA can rupture immediately, grow before rupturing, or remain stable. Predicting the evolution of an unruptured IA is very difficult. Indeed, the biology of the IA wall is complex and the precise biomechanical processes leading to aneurysm wall rupture are not yet known. While the contribution of wall shear stress in IA disease has been demonstrated in several studies, the role of cyclic circumferential stretch (CCS) remains poorly understood. Purpose The levels of CCS in saccular IAs are unknown but are generally considered very low or even absent. The goal of our study was to investigate the transcriptional response of endothelial cells (ECs) to absence of CCS and the potential impact on the endothelium function. Methods Human umbilical veins ECs (HUVECs) from 6 different donors were exposed to physiological CCS levels for cerebral arteries (6% stretch) or to aneurysmal CCS (0%) for 48h using the Flexcell strain unit FX-5000T, and unbiased transcriptomics were performed. The expression of selected genes was confirmed by qPCR. Results As a validation of our methodology, we verified the induction of eNOS phosphorylation after exposure of the ECs to physiological CCS. Stretched EC samples display a high similarity between each other while EC samples under aneurysmal CCS were spread-out on a multidimensional scaling plot. The differential gene expression of ECs exposed to aneurysmal or physiological CCS revealed 51 up-regulated genes and 49 down-regulated genes in absence of CCS. The gene set enrichment analysis identified 70 up-regulated and 38 down-regulated pathways in HUVECs exposed to aneurysmal CCS. Up-regulated pathways were involved in oxidative stress, angiogenic and inflammatory pathways, and the down-regulated pathways in proliferation and extracellular matrix-receptor interactions. We confirmed by qPCR the down-regulation by aneurysmal CCS of Gja4 and Gja5, genes coding for the gap junction proteins Connexin37 (Cx37) and Connexin40 (Cx40), respectively. Connexins (Cxs) are crucial proteins for endothelial homeostasis, vascular function, endothelial cell cycle regulation and inflammation, and their role in the context of IA disease will be further studied. Conclusion Our results indicate that physiological CCS prevents large deviation in ECs and regulate the expression of genes essential for maintaining vascular homeostasis. The down-regulation of endothelial Cx37 and Cx40 under aneurysmal CSS may contribute to the endothelial dysfunction associated with IA progression. Further investigation may help to better define the role of Cxs in aneurysmal disease and to understand the significance of absence of CCS in IA disease progression.
Role of organ-specific response to immune checkpoint inhibitor in survival for advanced hepatocellular carcinoma.
Authors: Kuo Wei Huang, Pei-Chang Lee, Yee Chao, I-Cheng Lee, Ming-Chih Hou, Yi-Hsiang Huang
Journal: Journal of Clinical Oncology (2022)

e16172 Background: Immune checkpoint inhibitors (ICIs) are encouraging treatment for advanced hepatocellular carcinoma. However, it is unclear which organ has the best response to ICIs as well as the role of individual organ response in survival for advanced HCC. We aimed to delineate tumor response to ICIs in different involved organs and its impact on survival. Methods: From May 2017 to October 2021, 224 patients received ICIs for advanced HCC were retrospectively reviewed. 174 patients who had follow-up images after ICIs, including 91 intrahepatic tumors only, 19 extrahepatic tumors only, and 66 concurrent intra- and extrahepatic tumors, were enrolled. Organ-specific responses were evaluated according to RECIST 1.1 and mRECIST criteria. Results: Of the 174 patients, 77 underwent anti-PD-1 monotherapy, the others received ICI combinations. The median overall survival (mOS) was 13.3 months (95% confidence interval [CI]: 11.4–15.3 months). Patients with concurrent intra- and extra-hepatic tumors had the lowest ORR and worse overall survival. The objective response rate (ORR) was the highest for metastatic lymph nodes (26%), followed by liver (24.2%), intra-abdominal tumors (21.4%), lung (12.1%), and bone (11.8%). Of the 66 patients with concurrent intra- and extrahepatic HCC, intrahepatic tumor response (HR: 0.247, P = 0.002) and ICI combinations (HR:0.403, p = 0.041) were significantly associated with a better OS in multivariate analysis. Conclusions: The response rate to ICIs was lower for lung and bone metastasis than liver and lymph nodes in advanced HCC. For patients with concurrent intra- and extrahepatic HCC, intrahepatic tumor response determines overall survival. [Table: see text]
Disparities in endometrial cancer clinical trial participation.
Authors: Emily Meichun Ko, Rafael Alvarez, Jonathan Heintz, Fiona Simpkins, Anna Jo Bodurtha Smith
Journal: Journal of Clinical Oncology (2022)

e18514 Background: Clinical trial participation may be a way to mitigate disparities in endometrial cancer. Our objective was to examine the association of clinical trial participation with patient, health system, and cancer factors in endometrial cancer. Methods: We conducted a retrospective cohort study of patients with endometrial cancer diagnosed from 2013-2021 using the nationwide de-identified electronic health record-derived Flatiron Health database. We used multi-level Poisson regression modeling to analyze the association of clinical trial participation (receipt of clinical trial drug) with patient, sociodemographic, health system, and cancer factors. Results: Of 4,662 patients with endometrial cancer, 3.9% (95% CI 3.3-4.5) were ever enrolled in a clinical drug trial. While Black patients accounted for 12% of endometrial cancers and 59% of high-risk histologies (MMT, serous, clear cell), only 3% were enrolled in clinical trials. Black patients were 57% less likely to enroll in a clinical trial (95%CI 0.26-0.72), and this disparity persisted in academic and community settings. Having a more aggressive cancer histology and living in the Southeast were associated with higher rates of clinical trial enrollment. Conclusions: Despite higher rates of aggressive cancer histologies, Black patients were disproportionately under-enrolled in endometrial cancer drug trials. Efforts to increase clinical trial diversity are needed.[Table: see text]
ATRT-08. SMARCB1- and SMARCA4-deficient malignant brain tumors with complex copy number alterations and<i>TP53</i> mutations may represent the first clinical manifestation of Li-Fraumeni syndrome
Authors: Martin Hasselblatt, Christian Thomas, Aniello Federico, Karolina Nemes, Pascal D Johann, Brigitte Bison, Susanne Bens, Uwe Kordes, Antje Redlich, Lienhard Lessel, Kristian W Pajtler, Christian Mawrin, Ulrich Schüller, Kay Nolte, Christof M Kramm, Felix Hinz, Felix Sahm, Caterina Giannini, Judith Penkert, Christian P Kratz, Stefan M Pfister, Reiner Siebert, Werner Paulus, Marcel Kool, Michael C Frühwald
Journal: Neuro-Oncology (2022)

Abstract Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant central nervous system tumor predominantly affecting infants. Mutations of SMARCB1 or (rarely) SMARCA4 causing loss of nuclear SMARCB1 or SMARCA4 protein expression are characteristic features, but further recurrent genetic alterations are lacking. Most AT/RTs occur de novo, but secondary AT/RTs arising in other central nervous system tumors have been reported. Malignant gliomas, IDH-wildtype, arising in patients with Li-Fraumeni syndrome typically show somatic mutations of TP53 as well as complex copy number alterations, but little is known about loss of SMARCB1 or SMARCA4 protein expression in this context. Here we report two children, in whom malignant supratentorial brain tumors with SMARCB1-deficiency, complex copy number alterations and somatic TP53 mutations lead to the discovery of pathogenic/likely pathogenic TP53 variants in the germ line. Screening of the molecularneuropathology.org data set for cases with similar genetic and epigenetic alterations yielded another case with SMARCA4-deficiency in a young adult with Li-Fraumeni syndrome. In conclusion, SMARCB1- or SMARCA4-deficient malignant brain tumors with complex copy number alterations and somatic TP53 mutations in children and young adults may represent the first clinical manifestation of Li-Fraumeni syndrome and should prompt genetic counseling and investigation for TP53 germline status.
The impact of mentoring on early career faculty: Assessment of a virtual mentoring program.
Authors: Akanksha Sharma, Heather Leeper, Soo Bang, Donna Molaie, Alyx B. Porter
Journal: Journal of Clinical Oncology (2022)

11039 Background: Participation in mentorship programs for early career physicians may be crucial to developing key skills and professional networks to navigate racial, ethnic and gender leadership disparities in medicine. A 6-month virtual facilitated peer mentorship program was developed and piloted through the Society for Neuro-Oncology (SNO) Women &amp; Diversity Committee. The evaluation of the program’s feasibility to positively impact early career physicians, investigators and trainees is presented here. Methods: We designed and conducted a virtual mentoring program pilot open to SNO’s multidisciplinary members in residency, fellowship, or early career phase, leveraging peer-mentoring sessions with mid-to late-career physician mentors. A curriculum with online resources was provided recommending groups meet for 6 sessions: 3 involving the mentor and 3 dedicated to peer-mentoring. Group assignments were based on time-zones and interests. Pre- and post-participation surveys assessed mentee experience. Descriptive statistics were used to assess participant demographics and survey results. Results: Our call for participation was broad; all 20 mentee applicants participated in 5 groups. Mentees were 90% women and 60% were from diverse racial and ethnic backgrounds. Most were aged 31-40 (75%) and junior faculty (50%) in neuro-oncology (65%). The 5 senior mentors (3 men and 3 of diverse race and ethnic backgrounds) practiced either neuro-oncology (3), neurosurgery (1) or radiation oncology (1). The proportion who reporting having a signature lecture increased from 15% to 62% during the pilot. A large majority reported their participation was worthwhile (85%), that they would participate again (92%) and would recommend it to others (92%). Feedback themes included positive personal growth, peer support, networking and job opportunities, access to CV reviews, lack of and desire for late career female mentors, and virtual scheduling constraints. While the pilot was limited by several variables, it was timely to connect participants in Q3 of 2020 early in the COVID-19 global pandemic. The virtual meeting environment created a venue to share and discuss topics such as work-life balance, burnout, leading through change and social connection. Despite not achieving 100% professional concordance, participants found the experience worthwhile. The tools and curriculum of topics provided was implemented differently across groups, leading to varied experiences. Finally, we did not have 100% post pilot follow up despite multiple attempts limiting our complete understanding of the pilot. Conclusions: This virtual mentorship pilot program proved feasible and of value in development of early career women and diverse individuals. A resource toolkit has been designed to scale and diffuse.
Inhibition of RhoA and Cdc42 by miR-133a modulates retinoic acid signaling during early development of the posterior cardiac tube segment
Authors: C Lopez-Sanchez, C Garcia-Padilla, V Garcia-Lopez, A Aranega, D Franco, V Garcia-Martinez
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Junta de Extremadura with FEDER co-financing. Introduction It has been demonstrated that multiple microRNAs play crucial roles in diverse biological processes, including cardiovascular development. In particular, we have previously observed miR-133a expressing at different stages of the primitive streak precardiac cells until the formation of the cardiac tube. MiR-133a role has also been reported as a modulator of proliferation and differentiation during heart development, involving many target genes and signaling pathways. Furthermore, we have shown in previous studies that retinoic acid plays a crucial role in cardiac development, modulating the expression of atrial markers. Purpose The aim of this work is to analyze the miR-133a modulation role on the retinoic acid signaling pathway in the posterior segment of the heart tube during cardiac looping formation. Methods By means of microinjections in both primitive endocardial tubes of chick embryo culture, gain- and loss-of-function experiments were performed with premiR-133a and anti-miR-133a, respectively. Subsequently, embryos were subjected to whole mount in situ hybridization with Tbx5 and AMHC1 probes, and qPCR. After TargetScan analysis and luciferase assays, immunohistochemistry was carried out by using anti-RhoA, -Cdc42 and -Raldh2/ALDH1A2 antibodies. Results Luciferase assays show that miR-133a is capable to recognize and bind to RhoA and Cdc42 3´UTR, thus triggering their mRNA degradation. Our results reveal that miR-133a gain-of-function experiments repress the expression of atrial markers Tbx5 and AMHC1, as well as RhoA, Cdc42 and -Raldh2/ALDH1A2 signals. Supporting these data, miR-133a loss-of-function experiments show the opposite effect: they increase the expression of Tbx5 and AMHC1, as well as RhoA, Cdc42 and Raldh2/ALDH1A2 signals. Conclusion Our results suggest that miR-133a could modulate negatively retinoic acid signaling by triggering degradation of pivotal genes RhoA and Cdc42, both required for Raldh2/ALDH1A2 expression, crucial to the synthesis of retinoic acid.
The recently emerged BA.4 and BA.5 lineages of Omicron and their global health concerns amid the ongoing wave of COVID-19 pandemic – Correspondence
Authors: Ranjan K. Mohapatra, Venkataramana Kandi, Ashish K. Sarangi, Sarika Verma, Hardeep Singh Tuli, Sandip Chakraborty, Chiranjib Chakraborty, Kuldeep Dhama
Journal: International Journal of Surgery (2022)